Process for the preparation of substituted carboxylic esters

ABSTRACT

A process for the preparation of 2(S)-alkyl-5-halogenpent-4-ene carboxylic esters by enzymatic hydrolysis, comprising the steps: a) enzymatic hydrolysis of racemic 2-alkyl-5-halogenpent-4-ene carboxylic esters in aqueous and alkaline medium in the presence of an esterase; b) isolation of 2(S)alkyl-5-halogenpent-4-ene carboxylic esters by extraction with an organic solvent; c) isolation of 2(R)-alkyl-5-halogenpent-4-ene carboxylic acids from the aqueous-alkaline medium; d) Esterification of 2(R)-alkyl-5-halogenpent-4-ene carboxylic acids, e) subsequent racemization to form 2-alkyl-5-halogenpent-4-ene carboxylic esters; and f) return of the racemate obtained in step e) to step a), if necessary together with fresh racemic 2-alkyl-5-halogenpent-4-ene carboxylic esters. The process permits the undesired R-stereoisomers to be converted into the desired 2(S)-alkyl-5-halogenpent-4-ene carboxylic esters to avoid waste product from the synthesis.

The invention relates to the preparation of2(S)-alkyl-5-halogenpent-4-ene carboxylic esters, in which the2(S)-stereoisomer is obtained by enzymatic hydrolysis of the racemate,followed by esterification then racemization of the resulting2(R)-alkyl-5-halogenpent-4-ene carboxylic acid, and returning theresulting racemic 2-alkyl-5-halogenpent-4-ene carboxylic ester to theprocess.

In EP-A-0 678 503, δ-amino-γ-hydroxy-ω-aryl-alkanecarboxamides aredescribed, which exhibit renin-inhibiting properties and could be usedas antihypertensive agents in pharmaceutical preparations.

In WO 01/09079, a multistep manufacturing process is described, in whichthe central intermediate is a 2,7-dialkyl-8-aryl-4-octenoylamide offormula A

and in particular of formula A1,

wherein R₁ and R₂ independently of one another are H, C₁–C₆alkyl,C₁–C₆halogenalkyl, C₁–C₆alkoxy, C₁–C₆alkoxy-C₁–C₆alkyl, orC₁–C₆alkoxy-C₁–C₆alkyloxy, R₃ is C₁–C₆alkyl, R₄ is C₁–C₆alkyl, R₆ isC₁–C₆alkyl, R₅ is C₁–C₆alkyl or C₁–C₆alkoxy, or R₅ and R₆ together aretetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH₂CH₂O—C(O)—substituted if necessary with C₁–C₄alkyl, phenyl or benzyl.

The compounds of formulae A and A1 are obtainable by reacting a compoundof formula B

as racemate or enantiomer, with a compound of formula C, as racemate orenantiomer,

wherein R₁ to R₄, R₅ and R₆ are as defined above, Y is Cl, Br or I and Zis Cl, Br or I, in the presence of an alkali metal or alkaline earthmetal. Y and Z are preferably Br and especially Cl.

In WO 01/09083, the compounds of formula C as racemates and2(S)-stereoisomers are described as well as their preparation. Thestereoisomers are obtained by hydrolysis of corresponding racemiccarboxylic esters to form their carboxylic acids, followed by racemateseparation by means of salt formation with chiral amine bases andcrystallization. A stereoselective synthesis is further described forthe preparation of 2(S)-pentene carboxylic acids and theirderivatization to form the corresponding pentene carboxylic acidhalides, esters and amides. This stereoselective synthesis of the estersis not yet satisfactory and is regarded as too costly.

The racemic compounds of formula D

are prepared as described in WO 01/09083 by coupling of 3-alkylbutanecarboxylic esters with trans-1-halogenmethyl-2-halogenethylene.Isolation of the 2(S)-alkyl-5-halogenpent-4-ene carboxylic ester is notdescribed, but only the possibility is disclosed of performing aracemate resolution of the carboxylic esters obtained in the synthesisby means of esterases, in which the very stable2(R)-alkyl-5-halogenpent-4-ene carboxylic acid is then formed as aby-product. It is extremely desirable to convert the entire racematedirectly into the 2(S)-carboxylic ester of formula D, especially sincethese carboxylic esters may be used in a new stereoselective synthesisfor the preparation of a central intermediate of formula A2

directly instead of the compound of formula C according to the abovecoupling reaction. These carboxylic esters may of course also beconverted to the 2(S)-carboxylic amides of formula C for use in theabove coupling reaction.

However, a fundamental disadvantage of racemate resolution remains. Notmore than 50% of the desired stereoisomer is obtainable. The2(R)-stereoisomer must be disposed of together with processing lossesarising from the racemate resolution. These large quantities makeracemate resolution completely uneconomical. A more effective method istherefore needed in which, above all, the occurrence of these largewaste disposal quantities is reduced or prevented.

It has now been surprisingly found that, in the preparation of2(S)-alkyl-5-halogenpent-4-ene carboxylic esters, the occurrence oflarge quantities of waste products can be avoided and even that onlyvery minor losses have to be expected using enzymatic racemateresolution, if the 2(R)-alkyl-5-halogenpent-4-ene carboxylic acid formedby enzymatic hydrolysis is isolated and returned to the separationprocess. The recycling ensures overall an extremely economical process,since the total yields are high and only unavoidable processing losseshave to be expected. The recycling also offers outstanding ecologicaladvantages, because the formation of waste products overall is reducedto a minimum, and a costly disposal of large quantities of synthesisproducts can be avoided.

The object of the invention is a process for the preparation of2(S)-alkyl-5-halogenpent-4-ene carboxylic esters by enzymatichydrolysis, comprising the steps

-   a) enzymatic hydrolysis of racemic 2-alkyl-5-halogenpent-4-ene    carboxylic esters in aqueous and alkaline medium in the presence of    an esterase;-   b) isolation of 2(S)-alkyl-5-halogenpent-4-ene carboxylic esters by    extraction with an organic solvent;-   c) isolation of 2(R)-alkyl-5-halogenpent-4-ene carboxylic acids from    the aqueous-alkaline medium;-   d) Esterification of 2(R)-alkyl-5-halogenpent-4-ene carboxylic    acids,-   e) subsequent racemization to form 2-alkyl-5-halogenpent-4-ene    carboxylic esters; and-   f) return of the racemate obtained in step e) to step a), if    necessary together with fresh racemic 2-alkyl-5-halogenpent-4-ene    carboxylic esters.

The 2(S)-alkyl-5-halogenpent-4-ene carboxylic esters may correspond toformula I,

wherein

-   R₁ is C₁–C₆alkyl, Z is chlorine, bromine or iodine, and the OR group    forms an ester group with the carbonyl residue.

The racemate may correspond to formula II,

wherein

-   R₁ is C₁–C₆alkyl, Z is chlorine, bromine or iodine, and the OR group    forms an ester group with the carbonyl residue.

The 2(S)-alkyl-5-halogenpent-4-ene carboxylic acid may correspond toformula III,

wherein

-   R₁ is C₁–C₆alkyl, and Z is chlorine, bromine or iodine.

R1 is preferably C₁–C₄alkyl. Examples of alkyl are methyl, ethyl, n- andi-propyl, n-, i- and t-butyl, pentyl and hexyl. It is very particularlypreferred when R₄ is i-propyl.

It is especially preferred when Z is Cl.

In the ester group, R is preferably an organic group with 1 to 18,preferably 1 to 12, and especially preferably 1 to 8 C-atoms and ifnecessary comprises heteroatoms selected from group O and N.

R may be a branched and preferably linear alkyl, which preferablycomprises 1 to 18, especially preferably 1 to 12, and—with particularpreference—1 to 6 C atoms. Some examples are methyl, ethyl, n-propyl,n-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,teradecyl, hexadecyl and octadecyl. Especially preferred are methyl andethyl. The alkyl may be substituted, for example with C₁–C₄alkoxy, suchas methoxy or ethoxy. Examples of substituted alkyl are methoxyethyl andethoxyethyl.

R may be cycloalkyl with 3 to 8, and preferably 5 or 6 ring-carbonatoms. Examples are cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl may besubstituted with C₁–C₄alkyl or C₁–C₄alkoxy.

R may be cycloalkyl-C₁–C₄alkyl with 3 to 8, and preferably 5 or 6ring-carbon atoms, which is unsubstituted or substituted with C₁–C₄alkylor C₁–C₄alkoxy. Examples are cyclopentylmethyl, cyclohexylmethyl,methylcyclohexylmethyl and cyclohexylethyl.

R may be C₆–C₁₀aryl which is unsubstituted or substituted withC₁–C₄alkyl or C₁–C₄alkoxy. Examples are phenyl, naphthyl, methylphenyl,ethylphenyl and i-propylphenyl.

R may be C₆–C₁₀aryl-C₁–C₄alkyl which is unsubstituted or substitutedwith C₁–C₄alkyl or C₁–C₄alkoxy. Examples are benzyl, methylbenzyl andphenylethyl.

Especially preferred compounds of formulae I, II and III are thosewherein Z is chlorine, R₁ is C₁–C₄alkyl and especially preferablyi-propyl. In compounds of formulae I and II, R is preferably C₁–C₄alkyl.

A quite especially preferred embodiment comprises compounds of formulaeI, II and III wherein Z is chlorine and R₁ is i-propyl, as well ascompounds of formulae I and II wherein R is methyl or ethyl.

Particularly preferred are compounds of formulae I and II wherein Z ischlorine, R₁ is i-propyl, and R is methyl or ethyl.

Process Step a)

The enzymatic hydrolysis of racemic carboxylic esters is known per seand familiar to a person skilled in the art. On hydrolysis, the propertyof the stereospecific hydrolysis of esterases is exploited to hydrolyseonly specific enantiomers by catalytic conversion. These esterases areknown and commercially available. The esterases are generally used incatalytic quantities, for example 0.001 to 10 and preferably 0.01 to 5percent by weight, related to the carboxylic acid. The reaction iscarried out in aqueous medium, in which the presence of pH buffers thatcan keep the pH value constant is favourable. It is expedient to adjustthe pH value to slightly alkaline, for example in the range more than 7to 10, preferably 7.5 to 9. The aqueous medium may contain organicsolvents miscible with water, especially alcohols such as methanol,ethanol, n- or i-propanol and butanol. Many buffer agents are known;phosphate buffers are especially suitable. The process may be carriedout at slightly elevated reaction temperatures, for example from roomtemperature to 60° C. It is expedient to conduct the hydrolysis usingdiluted bases of alkali metals and alkaline earth metals, especiallysodium or potassium hydroxide. The consumption of hydroxides can befollowed and the endpoint of the reaction thus determined. Aqueoushydroxide solutions may be added altogether or in portions, for exampledrop by drop.

Process Step b)

To isolate the non-hydrolysed carboxylic esters of formula I, an inertorganic solvent or solvent mixture which dissolves the ester and is notmiscible with water, and which can therefore be readily separatedthrough the formation of a two-phase system, is added to the reactionmixture. Suitable solvents are hydrocarbons (pentane, hexane,cyclohexane, methyl cyclohexane, benzene, toluene and xylene),halogenated hydrocarbons (methylene chloride, chloroform,tetrachloroethane), ketones (acetone, methyl isobutyl ketone), andethers (diethyl ether, di-n-propyl ether, dibutyl ether, i-propyl methylether, t-butyl methyl ether, ethylene glycol dimethyl ether,tetrahydrofuran and dioxan). Compounds of formula I may be isolated fromthe separated organic phase in the customary manner, for example bywashing and drying the organic phase, distilling off the used solventand if necessary purifying the resulting product by distillation. Thecarboxylic esters of formula I are obtained in almost theoretical yieldwith an enantiomeric purity of more than 99%.

Process Step c)

2(R)-Alkyl-5-halogenpent-4-ene carboxylic acids may be isolated fromaqueous-alkaline medium in a manner known per se, for example byprecipitating the acid or salts in a suitable medium, or preferably byextraction of the carboxylic acids. To this end, the basic reactionresidue is first acidified, for example with mineral acids such assulfuric acid or hydrochloric acid. An inert organic solvent or solventmixture is then added which dissolves the acid and is not miscible withwater and can therefore be readily separated by the formation of atwo-phase system. Suitable solvents are polar organic solvents, inparticular ether. After extraction, the organic phases can be washed anddried. The solvent is then removed, for example by distillation, ifnecessary in a vacuum. The residue remaining after removal of thesolvent can be used without further purification in in the next step d).2(R)-Alkyl-5-halogenpent-4-ene carboxylic acids are obtained in analmost quantitative yield.

Process Step d)

Esterification methods for carboxylic acids are generally known. Forexample, the esterification may be carried out with alcohols in thepresence of mineral acids such as hydrochloric acid or sulfuric acid,the addition of water-binding agents or azeotropic removal of thereaction water being advantageous. It is more expedient to useesterification agents such as diazoalkanes, dialkyl sulfates or acetals,especially activated acetals such as N,N-dimethylaminoformamide dialkylacetals, which may be used alone or together with appropriate alkalimetal alcoholates. The reaction may be performed without or in thepresence of inert solvents. The reaction is carried out at an elevatedtemperature, for example 40 to 150° C., preferably 50 to 100° C.

The carboxylic acids obtained in process step c) may be derivatizedbefore esterification, for example to form acyl halides, in particularchlorides and bromides. Halogenation reagents are known. Inorganichalides such as phosphorus pentachloride or thionyl chloride arefrequently used. The acyl halides may be esterified in a manner knownper se by reaction with alcohols either without or in the presence of asolvent. The esterification method is exothermic, and cooling of thereaction is advantageous at the start of the reaction. The reaction isthen performed at an elevated temperature, for example 40 to 150° C.,and preferably 50 to 100° C.

Process Step e)

The (R)-carboxylic ester obtained in process step d) does not need to beisolated for racemization. It is advantageous to perform theracemization in the same reaction vessel following esterification.Methods of racemization are known per se, for example heating to hightemperatures and/or adding strong bases. Preferably alkali metalalcoholates are used as bases, especially sodium or potassiumalcoholates. When selecting the alcohol for the alcoholate, it isexpedient to ensure that it corresponds to the alcohol in the estergroup of the (R)-carboxylic ester. If a (R)-carboxylic acid methyl esteris prepared, it is advantageous to use sodium or potassium methylate.The alcoholate may be used in catalytic to equimolar quantities, forexample 0.01 to 1 mol, in relation to the (R)-carboxylic ester. If theesterification is carried out with an alkali metal alcoholate via anacyl halide, the quantity of alkali metal alcoholate determined forracemization may already be added during esterification. In this case,racemization may already start to occur during esterification. Thereaction temperature may range for example from 40 to 150° C. andpreferably from 50 to 100° C. Under the specified conditions, completeracemization is achieved.

The process for isolation of the racemic carboxylic ester may be carriedout in a manner known per se. It is advantageous to use extractionmethods, as described earlier. The carboxylic esters are obtained inyields of 97% or more, the (R)-carboxylic acid of process step c) beingquantitatively converted to the corresponding racemic carboxylic ester.Racemization and esterification are performed consecutively in the samereaction vessel, which offers process engineering advantages.

Process Step f)

The residue obtained after removal of the solvent may be immediatelyreused as crude product in process step a). Using the process accordingto the invention, the desired (S)-carboxylic esters can be prepared withvery high yields and a high degree of chemical and optical purity, andthe undesired (R)-carboxylic acid which inevitably occurs in theseparation process can be converted to the desired (S)-carboxylicesters. Complete utilization of the synthesized racemic2-alkyl-5-halogenpent-4-ene carboxylic ester is thereby achieved, anddisposal of the undesired waste product of synthesis,(R)-2-alkyl-5-halogenpent-4-ene carboxylic acid, can be completelyavoided.

The following examples explain the invention in more detail.

A) Synthesis of racemic 2-alkyl-5-halogenpent-4-ene carboxylic estersEXAMPLE A1 Synthesis of

An agitated solution of 271.3 ml diisopropylamine and 1.6 l tert-butylmethyl ether is cooled to −10° C., and 768 ml 2.5 M n-hexyl lithiumsolution (in hexane) is added over a period of 15 minutes. The solutionis stirred for 5 minutes at −10° C., and then 211.2 ml methylisovalerate is added drop by drop over a period of 10 minutes. Thesolution is stirred for 15 minutes, and then 179.6 g potassiumtert-butylate in 260 ml 1,2-dimethoxyethane is added over a period of 15minutes at −10° C. The reaction mixture is stirred for 1 h at −5° C.,and then 195.3 g trans-1,3-dichloropropene is added drop by drop. Thereaction mixture is stirred for a further 3 hours at −5° C., and then600 ml aqueous 10 N HCl is added at 0° C. The organic phase is separatedoff and the aqueous phase extracted with tert-butyl methyl ether (2×0.5l). The organic phases are washed consecutively with 1N HCl (0.5 l) andaqueous NaCl solution, dried with sodium sulfate and concentrated byevaporation. By means of distillation, title compound A is obtained fromthe residue as a colourless oil (249.1 g, 79%). ¹H-NMR (300 MHz, CDCl₃,δ): 0.95 (m, 6H), 1.90 (m, 1H), 2.10–2.20 (m, 3H), 3.35 (s, 3H),5.80–6.0 (m, 2H) ppm.

B) Preparation of (S)-2-alkyl-5-halogenpent-4-ene carboxylic estersEXAMPLE B1 Preparation of

A solution of 225 g A in 94 ml isopropanol is added to 2.35 l phosphatebuffer (pH 7.0). In the presence of 9.42 ml (20700 U) pig liver esterase(Technical Grade, Roche Diagnostics), the mixture is agitated at pH 8.0and 40° C. until consumption of 623 ml 1.0 N NaOH. The reaction mixtureis mixed with tert-butyl methyl ether at room temperature and filteredvia Hyflo®. The organic phase is separated off and the aqueous phaseextracted with tert-butyl methyl ether (2×1 l). The organic phases arewashed consecutively with 5% aqueous Na₂CO₃ solution (3×0.7 l) andconcentrated saline (1×1 l), dried with 300 g Na₂SO₄, concentrated byevaporation and dried in a vacuum. By means of distillation, titlecompound B is obtained from the residue as a colourless oil (107.7 g,47%) with an ee greater than 99%. ¹H-NMR (300 MHz, CDCl₃, δ): 0.95 (m,6H), 1.90 (m, 1H), 2.10–2.20 (m, 3H), 3.35 (s, 3H), 5.80–6.0 (m, 2H)ppm.

C) Isolation of (R)-2-alkyl-5-halogenpent-4-ene carboxylic acids EXAMPLEC1 Preparation of

The alkaline aqueous phases obtained and combined as described underexample B1 are acidified at 0° C. with 4N HCl (1 l) and extracted withtert. butyl methyl ether (3×0.7 l). The organic phases are washed withwater (0.5 l) and aqueous NaCl solution, dried over sodium sulfate andconcentrated on a rotary evaporator. The residue (126 g) corresponds totitle compound C, which is used as crude product in examples D1 and D2.

D) Racemization to 2-alkyl-5-halogenpent-4-ene carboxylic esters

Example D1

Preparation of A, esterification with N,N-dimethylformamide dimethylacetal 106 g C (crude) is heated while stirring to 70° C. 136 mlN,N-Dimethylformamide dimethyl acetal is added drop by drop over aperiod of 30 minutes at 65–70° C. and stirred under reflux for a further2 hours. 55.6 ml sodium methylate (5.4 M in methanol) is added drop bydrop over a period of 5 minutes at reflux temperature and stirred underreflux for a further 2 hours. The reaction solution is cooled to roomtemperature, poured onto 1 l water and extracted with tert-butyl methylether (2×0.5 l). The organic phases are washed with water/aqueous NaClsolution (9:1; 1 l), dried over sodium sulfate and concentrated on arotary evaporator.

The residue 110.7 g (97%) corresponds to compound A. Completeracemization is demonstrated by gas chromatography (Lipodex® E,Macherey-Nagel).

EXAMPLE D2 Preparation of A Via Acyl Chloride

106 g C (crude) is heated while stirring to 60° C. 87.3 ml thionylchloride is added drop by drop over a period of 30 minutes at 60–70° C.(gas evolution) and stirred for a further 60 minutes at 70° C. Thethionyl chloride excess is distilled off under a slight vacuum (300–30mbar) and the residue obtained is cooled to 0° C. 60 ml methanol is thenadded drop by drop at 0 to not more than 8° C. over a period of 10minutes. 222 ml sodium methylate (5.4 M in methanol) is added drop bydrop at 8–12° C. (exothermic reaction) over a period of 20 minutes. Thereaction mixture is heated to reflux and agitated for a further 7 hours.The reaction solution is cooled to room temperature, poured onto icewater (1 l) and extracted with tert-butyl methyl ether (2×0.5 l). Theorganic phases are washed with water/aqueous NaCl solution (9:1; 1 l),dried over sodium sulfate and concentrated on a rotary evaporator. Theresidue 111.2 g (97%) corresponds to title compound A. Completeracemization is demonstrated by gas chromatography (Lipodex® E,Macherey-Nagel).

E) Recycling of Compounds A EXAMPLE E1:

The compound A prepared according to example D1 is subjected to racemateresolution with 115 g fresh compound A as described in example B1. Thesame separation result is obtained. The recycling as described inexamples C1 and D1 may then be continued.

EXAMPLE E2:

The compound A prepared according to example D2 is subjected to racemateresolution with 114 g fresh compound A as described in example B1. Thesame separation result is obtained. The recycling as described inexamples C1 and D2 may then be continued.

1. A process for the preparation of 2(S)-alkyl-5-halogenpent-4-enecarboxylic esters by enzymatic hydrolysis, comprising the steps a)enzymatic hydrolysis of racemic 2-alkyl-5-halogenpent-4-ene carboxylicesters in aqueous and alkaline medium in the presence of an esterase; b)isolation of 2(S)-alkyl-5-halogenpent-4-ene carboxylic esters byextraction with an organic solvent; c) isolation of2(R)-alkyl-5-halogenpent-4-ene carboxylic acids from theaqueous-alkaline medium; d) esterification of2(R)-alkyl-5-halogenpent-4-ene carboxylic acids to2(R)-alkyl-5-halogenpent-4-ene carboxylic esters, e) subsequentracemization to form 2-alkyl-5-halogenpent-4-ene carboxylic esters; andf) return of the racemate obtained in step e) to step a), if necessarytogether with fresh racemic 2-alkyl-5-halogenpent-4-ene carboxylicesters.
 2. The process according to claim 1, wherein2(S)-alkyl-5-halogenpent-4-ene carboxylic ester corresponds to formulaI,

wherein R is an organic group with 1 to 18 C-atoms, R₁ is C₁–C₆alkyl, Zis chlorine, bromine or iodine, and the OR group forms an ester groupwith the carbonyl residue.
 3. The process according to claim 1, whereinthe racemate used in process a) corresponds to formula II.

wherein R is an organic group with 1 to 18 C-atoms, R₁ is C₁–C₆alkyl, Zis chlorine, bromine or iodine, and the OR group forms an ester groupwith the carbonyl residue.
 4. The process according to claim 1, wherein2(R)-alkyl-5-halogenpent-4-ene carboxylic acid corresponds to formulaIII,

wherein R₁ is C₁–C₆alkyl and Z is chlorine, bromine or iodine.
 5. Theprocess according to claim 2, wherein Z is chlorine.
 6. The processaccording to claim 2, wherein R is C₁–C₁₈alkyl.
 7. The process accordingto claim 6, wherein the alkyl is methyl or ethyl.
 8. The processaccording to claims 2, wherein R₁ is C₁–C₄alkyl, and Z is chlorine. 9.The process according to claims 2, wherein Z is chlorine, R₁ isi-propyl, and R is methyl or ethyl.
 10. The process according to claim1, wherein the enzymatic hydrolysis in process step a) is performed withdiluted, aqueous KOH or NaOH.
 11. The process according to claim 1,wherein the isolation is performed by means of extraction with anorganic solvent which is not miscible with water.
 12. The processaccording to claim 1, wherein the 2(R)-alkyl-5-halogenpent-4-enecarboxylic acids are isolated by extraction with an organic solvent, thereaction mixture being acidified beforehand.
 13. The process accordingto claim 1, wherein the 2(R)-alkyl-5-halogenpent-4-ene carboxylic acidis either esterified with an esterification agent, or the carboxylicacid is converted to the acyl halide before esterification.
 14. Theprocess according to claim 1, wherein the racemization following theesterification after process step d) is performed in the same reactionvessel without isolation of the 2(R)-alkyl-5-halogenpent-4-enecarboxylic ester.
 15. The process according to claim 1, wherein theracemization is performed in the presence of an alkali metal alcoholateat elevated temperatures.
 16. The process according to claim 3, whereinZ is chlorine.
 17. The process according to claim 4, wherein Z ischlorine.
 18. The process according to claim 3, wherein R isC₁–C₁₈alkyl.
 19. The process according to claim 18, wherein the alkyl ismethyl or ethyl.
 20. The process according to claim 3, wherein R₁ isC₁–C₄alkyl, and Z is chlorine.
 21. The process according to claim 4,wherein R₁ is C₁–C₄alkyl, and Z is chlorine.
 22. The process accordingto claim 3, wherein Z is chlorine, R₁ is i-propyl, and R is methyl orethyl.
 23. The process according to claim 4, wherein Z is chlorine, R₁is i-propyl, and R is methyl or ethyl.